Heterologous Sarbecovirus Receptor Binding Domains as Scaffolds for SARS-CoV-2 Receptor Binding Motif Presentation

Year: 2024

Type: article

Abstract: Structure-guided rational immunogen design can generate optimized immunogens that elicit a desired humoral response. Design strategies often center on targeting conserved sites on viral glycoproteins that will ultimately confer potent neutralization. For SARS-CoV-2 (SARS-2), the surface-exposed spike glycoprotein includes a broadly conserved portion, the receptor binding motif (RBM), that is required to engage the host cellular receptor, ACE2. Expanding humoral responses to this site may result in a more potent neutralizing antibody response against diverse sarbecoviruses. Here, we used a "resurfacing" approach and iterative design cycles to graft the SARS-2 RBM onto heterologous sarbecovirus scaffolds. The scaffolds were selected to vary the antigenic distance relative to SARS-2 to potentially focus responses to RBM. Multimerized versions of these immunogens elicited broad neutralization against sarbecoviruses in the context of preexisting SARS-2 immunity. These validated engineering approaches can help inform future immunogen design efforts for sarbecoviruses and are generally applicable to other viruses.

Source: ACS Infectious Diseases

DOI: 10.1021/acsinfecdis.3c00483

Authors: Blake M. Hauser, Maya Sangesland, Evan C. Lam, Kerri J. St Denis, Maegan L. Sheehan, Mya L. Vu, Agnes H. Cheng, Sophia Sordilla, Dana Thornlow Lamson, Ahmad W. Almawi, Alejandro B. Balazs, Daniel Lingwood, Aaron G. Schmidt

Institutions: Ragon Institute of MGH, MIT and Harvard, Massachusetts Institute of Technology, Harvard University

Language: English

Topic: SARS-CoV-2 and COVID-19 Research

Subfield: Infectious Diseases

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: hybrid

Estimated APC paid: $4,500

Funders: Charles H. Hood Foundation, Gilead Sciences, Centers for Disease Control and Prevention Foundation, Massachusetts Consortium on Pathogen Readiness, National Institutes of Health, National Institute on Drug Abuse, National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases

OpenAlex ID: W4391289923